Poly(ethylene glycol) derivatives for metal-free click chemistry

Abstract

The present invention provides bifunctional polymers, methods of preparing the same, and intermediates thereto. These compounds are useful in a variety of applications including the PEGylation of biologically active molecules. The invention also provides methods of using said compounds and compositions thereof.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         n is 5-2500; 
         R 1  and R 2  are each independently hydrogen, halogen, NO 2 , CN, —N═C═O, —C(R)═NN(R) 2 , —P(O)(OR) 2 , —P(O)(X) 2 , a 9-30 membered crown ether, or an optionally substituted group selected from aliphatic, a 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety, wherein:
 one of R 1  or R 2  is a moiety suitable for metal-free click chemistry; 
 
         each X is independently halogen; 
         each R is independently hydrogen or an optionally substituted selected from aliphatic or a 3-8 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         L 1  and L 2  are each independently a valence bond or a bivalent, saturated or unsaturated, straight or branched C 1-12  hydrocarbon chain, wherein 0-6 methylene units of L 1  and L 2  are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —SO—, —SO 2 —, —NRSO 2 —, —SO 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—, wherein:
 each -Cy- is independently an optionally substituted 3-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein R 1  is an activated alkyne, oxanobornadiene, or oxime (as a nitrile oxide precursor). 
     
     
         3 . The compound according to  claim 2 , wherein R 1  is —CH═N—OH, 
       
         
           
           
               
               
           
         
       
       or 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein R 2  is an activated alkyne, oxanobornadiene, or oxime (as a nitrile oxide precursor). 
     
     
         5 . The compound according to  claim 4 , wherein R 2  is —CH═N—OH, 
       
         
           
           
               
               
           
         
       
       or 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound selected from any depicted in Tables 1 through 10.